Solid dosage forms for pharmaceuticals such as tablets and capsules require the use of fine powders of drug substance material in order to achieve uniform distribution of the pharmacologic agent in these powder-based formulations. Additionally, drug substances with very low solubility and dissolution rates often need to be reduced in size to levels on the order of 10 μm or less in order to achieve satisfactory bioavailability. In some cases, particles <1 μm are necessary for drugs with exceptionally poor aqueous solubility.
Conventional techniques for the processing of drug substance particles from solutions suffer from many disadvantages. Recrystallization, freeze drying and spray drying require solvent evaporation. Drying techniques can leave residual amounts of solvent and the use of heat to aid drying can cause thermal degradation of the drug substance. Mechanical milling to reduce particle size can also cause thermal degradation. All of these techniques can result in particle size variability.
Improved methods for generating micron and sub-micron size particles with narrow particle size distribution using supercritical fluids (SCFs) such as CO2 have been disclosed (see for example U.S. Pat. No. 5,833,891 and H. S. Tan and S. Borsadia, Expert Opinion on Therapeutic Patents, 2001, 11, 861-872). Methods include Supercritical Fluid Extraction (SFE), Rapid Expansion of Supercritical Solutions (RESS), Gas Anti-Solvent Recrystallization (GAS), as well as Supercritical fluid Antisolvent (SAS).
A supercritical fluid (SCF) is a substance above its critical temperature and critical pressure (31° C., 1,070 psi for CO2). A SCF such as CO2 is essentially a compressed, high diffusivity and high density fluid at mild temperature. It is relatively innocuous, inexpensive, and unreactive. SFE is often used to selectively extract a variety of compounds. After extraction, the SCF mixture is expanded into a collection vessel held at a lower pressure. Because of the low solvent power of the low-pressure gas, the compound precipitates and is collected in a vessel. The effluent low pressure gas is vented out or recycled into the process. A wealth of information on the properties of SCFs is available in the technical literature (McHugh, M. and Krukonis, V., Supercritical Fluid Extraction, Principles and Practice, 2nd Ed., Butterworth-Heinemann, Boston. 1993).
At the heart of every particle formation technique utilizing SCFs is their ability to dissolve in or solubilize a particular solvent or substance. Although SFE has been used to produce pharmaceutical powders (Larson, K. A. et al., Biotechnology Progress 2 (2), June 1986, pp. 73-82), it is normally used for selective extraction of SCF-soluble material from raw substrates where the particle size of the extracted material following depressurization is generally not a concern of the process. A particularity of SFE is that it can be used to extract desirable materials as well as impurities in any physical form: liquid, solid or semisolid.
The concept that material dissolved in a SCF can be precipitated by rapid reduction in pressure has been known for over a century (J. B. Hannay and J. Hogarth, “On the solubility of solids in gases”, Proceedings of the Roy. Soc. London, 29, 324-326, 1879). The RESS process (U.S. Pat. No. 4,582,731) takes advantage of this property of SCFs to crystallize desirable solid substances for which particle size and possibly other physical and bulk characteristics are a main concern.
In the RESS process, similar to SFE, a solute substance is placed in a high-pressure vessel. A SCF is then pumped through the vessel to dissolve the substance and form a solution of the substance in the SCF. The fluid mixture is then expanded through a nozzle into a vessel held at a substantially lower, sub-critical pressure where the fluid is now a low density gas. Because of the low solvent power of the low-pressure gas, the substance precipitates and is collected in the vessel. The large pressure differential across the nozzle causes the expansion to take place at ultrasonic velocity and supersaturation to increase rapidly. The rapid expansion translates into a rapid change in the density and solvent power of the fluid and therefore into rapid crystallization rates which result in the formation of small microparticles and nanoparticles of the substance. Effluent gas is passed through a micro-filter and then vented or recycled. An alternative way to rapidly reduce the solvent power of the SCF without any substantial change in pressure consists of contacting the SCF solution with an inert gas such as nitrogen or helium where the solute substance is substantially insoluble. The inert gas may be kept at a pressure similar to that of the SCF solution. The inert gas rapidly mixes with the SCF to cause its solvent power to decrease and the solute to precipitate.
For material that has little solubility in a SCF of choice, the SCF may be used as an antisolvent. The GAS process (U.S. Pat. No. 5,360,478; U.S. Pat. No. 5,389,263) was first reported at an international meeting of the American Institute of Chemical Engineers (Paper 48c at the AlChE Meeting, Nov. 29, 1988) and later by Gallagher, P. M. et al. (Chap 22, Supercritical Fluid Science and Technology, ACS Symposium Series, 406, Washington, D.C., K. P. Johnston, J. M. L. Penninger, ed., ACS Publishing, 1989). In GAS, a SCF is used as an antisolvent to process a SCF-insoluble solute from a pre-mixed batch of an organic solution of the solute by adding a SCF into the solution. Addition of the SCF causes its concentration in the solution to increase and the solution to expand. Solute precipitation takes place when the solution becomes supersaturated.
The batch GAS process is limited in its ability to process large quantities of material. In the SAS process, the organic solution of the solute is added continuously to continuously flowing SCF antisolvent. The organic solvent rapidly mixes and dissolves in the SCF to form a homogeneous high-pressure fluid mixture. Because the solute is substantially insoluble in the SCF and the SCF and the organic solvent are miscible, this results in its precipitation in the high pressure vessel. The SCF-organic solvent mixture is passed through a micro-filter and then expanded into a low pressure vessel where the SCF separates from the organic solvent.
Because of the relatively low processing temperature, the SAS process is suitable for processing thermally labile substances. Unlike other processes such as conventional spray drying where the rate of solvent removal from droplet surfaces is relatively slow and depends to a large extent on processing temperature, in this process such rate depends primarily on the density and flow rate of the SCFs. Both parameters can easily be controlled over a wide range at a relatively low temperature to control the rate of solvent removal over an equally wide range. Several variants of the SAS process have been developed. Coenen et al. (U.S. Pat. No. 4,828,702) report a countercurrent process whereby a liquid solution of a solid solute is sprayed into a SCF antisolvent such as CO2 to recover the solid material as a powder. Fisher and Muller (U.S. Pat. No. 5,043,280) report a process whereby a liquid solution of active substance is sprayed as a fine mist into a SCF solution of a carrier material to produce sterile microparticles of active substance embedded within carrier material. Yeo et al. (Biotechnology and Bioengineering, 1993, Vol. 41, p. 341) and Debenedetti (U.S. Pat. No. 6,063,910) also describe a process whereby the solution is sprayed as a fine mist across a nozzle into a high pressure vessel containing a SCF in order to produce fine powders of the solute. Schmidt (U.S. Pat. No. 5,707,634) reports a process whereby a non-sterile solute is recovered from a solution injected into a high-pressure vessel containing a SCF antisolvent. Subramaniam et al. (U.S. Pat. No. 5,833,891) describe a process whereby an ultrasonic nozzle is used to enhance the atomization of the liquid solution spray which aids in the production of finely divided microparticles and nanoparticles of active material.
The SAS process has also been identified in the literature as “Aerosol Solvent Extraction Systems” (ASES) and a variation thereof has been identified as “Solution-Enhanced Dispersion by SCFs” (SEDS). See Tan and S. Borsadia, Expert Opinion on Therapeutic Patents, 2001, 11, 861-872.
SEDS (U.S. Pat. Nos. 5,851,453 and 6,063,138) involves using a coaxial, non-ultrasonic nozzle. High mass transfer rates are achieved with a high ratio of supercritical fluid to solvent and the high velocities of the SCF facilitate the atomization of the solution. Particles produced using SCFs have also been used to coat substrates. Subramaniam et al. (U.S. Pat. No. 5,833,891) describe a process whereby particles are crystallized from a liquid solution and directed at a bed of fluidized core particles to form a coating. In this process, the SCF is used to both fluidize the core particles and to effect the crystallization of the coating substance out of the solution. The process can be used in a manner similar to the classic Wurster coating process. Benoit et al. (U.S. Pat. No. 6,087,003) describe a batch process whereby an active substance is stirred in a high pressure vessel containing a SCF and a coating material dissolved therein. The temperature of the SCF is then gradually lowered to a point where it separates into a gas phase and a liquid phase where the core particles are in suspension and the coating material is in solution. Continuous removal of the gas phase causes the concentration of the coating material in the liquid phase to increase and its solubility to decrease. This results eventually in the precipitation of the coating material on the active substrate. Because of the possibly limited solubility of coating material in a batch of SCF, the process may be repeated using pre-loaded coating material attached to the shaft of the stirring device. Smith (U.S. Pat. No. 4,582,731) discusses a process whereby particles formed by RESS are directed at and adhered to solid surfaces such as glass, fused silica and platinum to form a thin film coating.
Processes described above are designed to produce either coated substrates or microparticles or microcapsules of a particular substance. A premise for the present invention is that in the pharmaceutical industry, fine drug powders are rarely used as final solid state formulations because collection, handling, flow, and/or compression of powders of microparticles and nanoparticles can be very challenging. A micronized powder of a particular drug substance is therefore rarely used without further processing. If one desires to make a solid state pharmaceutical formulation of a drug substance, it is generally necessary to mix the drug microparticles or nanoparticles with particles of carrier substance(s). Such carriers, such as lactose, exhibit good handling, flow, and compression properties. After mixing with a carrier, granulation is often used in the pharmaceutical industry to produce free-flowing, dust-free granules from fine powders and to improve the uniformity of drug distribution in the product (Handbook of Pharmaceutical Granulation Technology, Marcel Dekker, N.Y., Dilip, M. P. Editor, Vol. 81, 1997). Current processes using SCFs to process fine powders do not address these issues. The following are some limitations of current processes:    1. Current processes do not address the difficulty of trapping fine particles upon their formation. They are designed to precipitate discrete small microparticles and nanoparticles which are normally difficult to trap in a processing vessel. Retention of such particles on filters is difficult and may result in filter plugging and/or reduction in throughput.    2. Current processes do not address the issues associated with the tendency of fine powders to agglomerate. In the SAS process, where particles crystallize rapidly, wet particles may come in close contact with each other and fuse or agglomerate. Similarly, in RESS, semi-solid or adhesive particles cannot be satisfactorily processed because they would rapidly agglomerate. Irrespective of the physical characteristics of the material, microparticles and nanoparticles of material exhibiting high surface free energy will tend to agglomerate and fuse to form large particles when in close contact. When processing drug substances, agglomeration can increase the effective particle size and result in lower drug dissolution rate and bioavailability. Agglomeration of crystallized material limits its effectiveness for coating small micron- and nanometer-sized particles. The utility of current processes is therefore limited in this regard.    3. Current processes designed to coat core particles with precipitated fine powders in a fluidized bed are difficult to control. Such processes do not address fine particle retention or the ability to coat fine powders which are notoriously difficult to fluidize. Fluidized beds require special equipment and controls that are not easily amenable for use with SCFs. The purpose of fluidizing the core particles is to suspend them so that they may be coated and dried preferably before coming in contact with another core particle, thereby minimizing agglomeration. Coating of core particles by this process can be achieved for many powders, but normally may require a great deal of process control. Specialized fluidization equipment normally does not allow for stirring but provides for a carefully controlled pressure differential within the vessel to effect fluidization of particles, uniform distribution of the fluidizing gas, control of bed expansion, and collection of fines. The superficial velocity of suspending fluid is critical; too high a velocity will cause the core particles to become entrained onto the filter; too low a velocity may result in incomplete expansion/fluidization of the bed. Because precipitation and drying happens very quickly in SCF processing, the droplets may be dried prior to contacting the core particles and the very small crystals that are produced can easily be entrained in the suspending fluid. Therefore, precipitation with adhesion to the core particles may not occur consistently, and some precipitated particles may become separated from the bed of core particles. The expansion and fluidization of a powder bed also requires longer and larger processing vessels, a major concern with high pressure equipment. Some powders may be more difficult to fluidize because of the enormous number of possible particle-particle interactions and changes in bed properties such as particle size distribution as particles are formed and others are coated. Core particles smaller than 10 μm often form unstable fluidized beds. Small particles may act as if damp, forming agglomerates or fissures which may result in spouting. Such processing difficulties are at least partially responsible for the limited use that fluidized bed processing has found in pharmaceutical processing. The technical literature provides a full account of the problems associated with fluid bed processing of small particles.
A drawback of RESS, GAS and SAS processes is the difficulty of trapping, collecting and handling fine powders of microparticles and nanoparticles. Filters used in these processes are generally not capable of effectively retaining the produced microparticles and nanoparticles. If filter pores are small enough to retain such particles, the filter can become rapidly plugged up by the particles. This can severely restrict flow through the crystallization vessel, and frequent interruptions to clean or replace filters may become necessary. In the case of RESS, resistance to flow causes pressure in the vessel to rise appreciably and the pressure drop across the nozzle to decrease. At some point, the pressure drop vanishes completely and the process would need to be halted. In the case of SAS, resistance to flow could also cause pressure in the vessel to continuously rise throughout the process. Even if microparticles can be retained by such devices as cyclones, they present handling difficulties. Flow characteristics of powders containing microparticles and/or nanoparticles are generally poor. Such powders may therefore be difficult to discharge and use in downstream processes. Further processing by such processes as mixing with carrier material and granulation may therefore still be necessary before incorporation into a formulation. Powders with poor flow characteristics are difficult to incorporate into carrier material and normally require special blending procedures or techniques to obtain the required blend uniformity. Fine powders are also difficult to handle because of their dustiness. Special operator protection is required and very specific procedures are required for potent drugs or toxins.